The present invention relates to cephem compounds having a broad antibacterial spectrum over various pathogenic bacteria and to pharmaceutical compositions containing the same. The compounds of the present invention are particularly efficacious against MRSA (methicillin resistant S. aureus).
Study of so-called broad spectrum cephem compounds having potent antibacterial activities against various Gram-positive and Gram-negative bacteria has recently been focused on cephem compounds at which 7-side chain is substituted with aminothiazole or aminothiadiazole and 3-position with a cyclic-type quarternary ammoniummethyl group. For example, the known 7-aminothiazole types include cefepime hydrochloride (U.S. Pat. No. 4,406,899), cefpirome sulfate (U.S. Pat. No. 4,609,653, JP(A) S57-192394), and cefoselis sulfate (JP(A) H07-196665, WO97/41128), and the 7-aminothiadiazole types include cefclidin (U.S. Pat. No. 4,748,171), and cefozopran hydrochloride (U.S. Pat. No. 4,864,022, JP(A) S62-149682, JP(A) H03-47189). These cephem compounds show almost none or extremely weak activities against MRSA which has been a clinical concern.
The other documents, disclosing the same types of cephem compounds, include, for example, JP(A) 4789/1983, JP(A) 155183/1985, JP(A) 97982/1985, JP(A) 97983/1985, JP(A) 24389/1982, JP(A) 57390/1983, JP(B) 65350/1991, JP(B) 14117/1992, JP(A) 231684/1985, JP(A) 30786/1987, WO92/22556, JP(A) 222058/1993, JP(A) 157542/1994, JP(A) 101958/1995, and JP(A) 101960/1995.
Among them, JP(A) 4789/1983 discloses cephem compounds which have an optionally substituted and 2 or more N atoms-containing heterocycle cation at the 3-position. JP(A) 155183/1985 discloses cephem compounds which have a 2 or more N atoms-containing and unsaturated condensed heterocycle cation at the 3-position. These documents, however, describe or suggest no concrete embodiment of a cephem compound having an imidazopyridiniummethyl group at the 3-position.
Though JP(A) 105685/1985, equivalent to J. Med. Chem. 1990, 33, P2114-2121, discloses cephem compounds having an imidazopyridiniummethyl group at the 3-position, any of the 3-substituents of the working example compounds is limited to imidazo[4,5-c]pyridiniummethyl. On the other hand, a compound having an imidazo[4,5-b]pyridiniummethyl group at the 3-position is shown by the chemical name without any physical data or the like. Further, the [4,5-b]-type compounds have only aminothiazole group as part of the 7-side chain. Namely, the document does not concretely describe a cephem compound at which 3-position is substituted with an imidazo[4,5-b]pyridiniummethyl group and 7-side chain with aminothiadiazole.
Therefore, it has been desired to develop cephem compounds of broad antibacterial spectrum which have anti-MRSA activity applicable enough to clinical use.
The present inventors have intensively studied to find out that introduction of an imidazo[4,5-b]pyridiniummethyl group into the 3-position of cephem compounds leads to broad antibacterial spectrum and excellent anti-MRSA activity, and have accomplished the present invention shown below.
(1) a compound of the formula (I): 
wherein,
X is N or CY and Y is H or halogen;
R1 is amino or protected amino;
R2 is hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl;
R3 is hydrogen, hydroxy, halogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio or optionally substituted amino;
R4 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkyl(lower)alkyl or an optionally substituted N-containing heterocyclic group;
R5 is hydrogen, amino, optionally substituted lower alkyl, optionally substituted lower alkoxy or optionally substituted lower alkylthio, or R4 and R5 taken together may form lower alkylene in which an optional hetero atom(s) intervene; and
a wavy line means syn- or anti-isomerism or a mixture thereof, an ester, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof (herein after may be referred to as compound (I)).
(2) the compound described in above (1) wherein X is N.
(3) the compound described in above (1) wherein R1 is amino.
(4) the compound described in above (1) wherein R2 is hydrogen or optionally substituted lower alkyl.
(5) the compound described in above (4) wherein R2 is lower alkyl optionally substituted with halogen.
(6) the compound described in above (1) wherein R3 is hydrogen.
(7) the compound described in above (1) wherein R4 is hydrogen, optionally substituted lower alkyl or an optionally substituted N-containing heterocyclic group.
(8) the compound described in above (7) wherein R4 is hydrogen, lower alkyl optionally substituted with amino, lower alkylamino or hydroxy(lower) alkylamino, or an optionally substituted 4- to 6-membered N-containing saturated heterocyclic group.
(9) the compound described in above (1) wherein R5 is hydrogen.
(10) the compound described in above (1) wherein the wavy line means syn-isomerism.
(11) the compound described in above (1) wherein X is N; R1 is amino; R2 is hydrogen or optionally substituted lower alkyl; R3 is hydrogen; R4 is hydrogen, optionally substituted lower alkyl or an optionally substituted N-containing heterocyclic group; R5 is hydrogen; and the wavy line means syn-isomerism.
(12) the compound described in above (11) wherein X is N; R1 is amino; R2 is hydrogen or lower alkyl optionally substituted with halogen; R3 is hydrogen; R4 is hydrogen, lower alkyl optionally substituted with amino, lower alkylamino or hydroxy(lower)alkylamino, or an optionally substituted 4- to 6-membered N-containing saturated heterocyclic group; R5 is hydrogen; and the wavy line means syn-isomerism.
(13) the compound described in above (12) wherein X is N; R1 is amino; R2 is hydrogen, xe2x80x94CH3, xe2x80x94CH2F, xe2x80x94CH2CH3 or xe2x80x94CH2CH2F; R3 is hydrogen; R4 is hydrogen, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94(CH2)2CH3, xe2x80x94(CH2)3NH2, xe2x80x94(CH2)3NHCH3, xe2x80x94(CH2)3NH(CH2)2OH, azetidinyl, pyrrolidinyl or piperidyl; R5 is hydrogen; and the wavy line means syn-isomerism.
(14) the compound described in above (13) wherein X is N; R1 is amino; R2 is hydrogen, xe2x80x94CH2F or xe2x80x94CH2CH3; R3 is hydrogen; R4 is hydrogen, xe2x80x94(CH2)3NH2, xe2x80x94(CH2)3NHCH3 or xe2x80x94(CH2)3NH(CH2)2OH; R5 is hydrogen; and the wavy line means syn-isomerism.
(15) the compound described in above (14), a pharmaceutically acceptable salt or hydrate thereof wherein X is N; R5 is amino; R2 is xe2x80x94CH2F; R3 is hydrogen; R4 is xe2x80x94(CH2)3NHCH3; R5 is hydrogen; and the wavy line means syn-isomerism.
(16) the compound described in above (15) which is a sulfate or a hydrate thereof.
(17) the compound described in any of above (1) to (16), which shows an antibacterial activity against Gram-positive bacteria including MRSA and Gram-negative bacteria.
(18) the compound described in (17) of which MIC50 value against MRSA is 50 xcexcg/ml or less.
(19) A method for preparing the compound described in any of above (1) to (18), which comprises reacting a compound of the formula(V): 
wherein R6 is a leaving group and the other symbols are the same as defined above, an ester, or a salt thereof with a compound of the formula(IV): 
wherein each symbol is the same as defined above, followed by optional deprotection.
(20) a compound of the formula(IV): 
wherein each symbol is the same as defined above.
(21) the compound described in above (20) wherein R3 is hydrogen; R4 is xe2x80x94(CH2)3NRaCH3 wherein Ra is H or an amino-protecting group; and R5 is hydrogen,
(22) a pharmaceutical composition which contains a compound described in any of above (1) to (18).
(23) a composition for use as an antibacterial agent which contains a compound described in any of above (1) to (18).
(24) a method for preventing or treating bacterial infectious diseases, which comprises administering a compound described in any of above (1) to (18).
(25) use of the compound described in any of above (1) to (18) for preparing a composition for use as an antibacterial agent.
Terms used herein are explained below. Unless otherwise mentioned, each term, by itself or as part of another, has a common meaning.
(Definition of X)
X is preferably N or CH, and more preferably N. Examples of halogen shown by Y include F, Cl, and Br and preferred is Cl.
(Definition of R1)
The protecting group of protected amino may be that known in the present field, such as C1xcx9cC6 alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, pivaroyl, and succinyl), C3xcx9cC5 alkenoyl (e.g., acryloyl, crotnoyl, and cinnamoyl), C6xcx9cC10 arylcarbonyl (e.g., benzoyl, naphthoyl, p-toluoyl, and p-hydroxybenzoyl), heterocyclylcarbonyl group (example of the heterocyclyl: e.g., 2-pyrrolyl, 3-pyrazolyl, 4-imidazolyl, 1,2,3-triazolyl, 1H-tetrazolyl, 2-furyl, 3-thienyl, 4-oxazolyl, 3-isooxazolyl, 2-pyrrolidinyl, 3-pyridyl, and 4-pyridazinyl), C1xcx9cC6 alkylsulfonyl (e.g., methanesulfonyl and ethanesulfonyl), C6xcx9cC10 arylsulfonyl (e.g., benzenesulfonyl, naphthalenesulfonyl, and p-toluenesulfonyl), substituted oxycarbonyl (e.g., methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-cyanoethoxycarbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, p-chlorophenoxycarbonyl, benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-butoxycarbonyl (Boc), and 2-propenyloxycarbonyl), substituted silyl (e.g., trimethylsilyl and tert-butyldimethylsilyl), and optionally substituted aralkyl (e.g., p-methoxybenzyl (PMB) and benzhydryl (BH)). One or two of the protecting group, preferably one, may bond to an amino group. A preferred R1 is amino in the light of the antibacterial activity.
(Definition of R2)
Lower alkyl includes a straight or branched C1 to C6 alkyl such as methyl, ethyl, n-propyl, i-propyl, t-butyl, n-pentyl, and n-hexyl, and preferred is C1 to C3 alkyl, more preferred is methyl, ethyl or n-propyl.
Cycloalkyl includes C3 to C7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
When the above lower alkyl or cycloalkyl is substituted, examples of the substituent include halogen (e.g., F, Cl, and Br), hydroxy, carboxy, cyano, amino, carbamoyloxy, sulfamoyl, lower alkoxycarbonyl (e.g., methoxycarbonyl, and ethoxycarbonyl), lower alkylthio (e.g., methylthio, and ethylthio), and preferred is halogen, esp., F. The number of the substituent is one or more.
Preferable R2 includes hydrogen and optionally substituted lower alkyl (e.g., CH3, CH2F, CH2CH3, and CH2CH2F), and more preferred is lower alkyl substituted with halogen (e.g., CH2F). The wavy line of xe2x80x9cxe2x80x94OR2xe2x80x9d preferably means syn-isomerism for the 7-amido bond part.
(Definition of R3)
Examples of halogen include F, Cl, Br and I.
Examples of lower alkyl include the above lower alkyl defined for R2, and preferred is methyl.
Examples of lower alkoxy include oxy bonding to lower alkyl, such as methoxy, ethoxy, n-propoxy, i-propoxy, t-butoxy, n-pentyloxy, and n-hexyloxy.
Examples of lower alkylthio include thio bonding to the lower alkyl, such as methylthio, ethylthio, n-propoxy, i-propylthio, t-butylthio, n-pentylthio, and n-hexylthio.
When the above lower alkyl, lower alkoxy or lower alkylthio is substituted, examples of the substituent include halogen (e.g., F, Cl, and Br), hydroxy, carboxy, cyano, amino, carbamoyloxy, sulfamoyl, lower alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), and lower alkylthio (e.g., methylthio and ethylthio).
Examples of the substituent of xe2x80x9coptionally substituted aminoxe2x80x9d include the above-described lower alkyl (e.g., methyl and ethyl) and the above-described amino-protecting group, and one or two of the substituents may be located on the amino.
R3 may be located at any of the 2- to 4-positions of the pyridinium ring. R3 is preferably hydrogen.
(Definition of R4)
Lower alkyl and cycloalkyl are the same as the above-described lower alkyl and cycloalkyl, respectively, which are defined for R2. Cycloalkyl(lower)alkyl means lower alkyl bonding to the cycloalkyl, such as cyclopropylmethyl, 1-cyclopropylethyl, 3-cyclopropylpropyl, cyclobutylmethyl, cyclopentylethyl and 3-cyclohexylpropyl.
Examples of lower alkenyl include a straight or branched C2 to C6 alkenyl, such as vinyl, aryl, 1-propenyl, i-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl1-propenyl, 2-methyl2-propenyl, 1-pentenyl, and 2-hexenyl, and preferred is aryl.
Lower alkoxy is the same as the above-described lower alkoxy defined for R3.
When each of the above lower alkyl, lower alkenyl, lower alkoxy, cycloalkyl and cycloalkyl(lower)alkyl is substituted, examples of the substituent include one or more, same or different, group(s) selected from hydroxy, optionally substituted carbamoyl (wherein the substituent is methyl, ethyl, propyl or xe2x80x94(CH2)3CH(NH2)CONH2), halogen (e.g., F and Cl), xe2x80x94CO(CH2)nCH(NH2)CONH2(n=1 to 3), optionally substituted amino wherein the substituent is lower alkyl (e.g., methyl, ethyl, and propyl), lower alkenyl (e.g., aryl), cycloalkyl (e.g., cyclopropyl), lower alkoxycarbonyl (e.g., t-butoxycarbonyl), hydroxy(lower)alkyl (e.g., hydroxymethyl, 1-hydroxyethyl, and 2-hydroxyethyl), sulfonic acid-oxy(lower)alkyl (e.g., 2-sulfonic acid-oxyethyl) or amino(lower)alkyl (e.g., 2-aminoethyl)), lower alkoxy (e.g., methoxy, ethoxy, and propoxy), lower alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), and N-containing heterocyclic group which is mentioned below wherein preferable is azetidinyl, pyrrolidinyl, piperidinyl, pyridyl or the like.
The N-containing heterocyclic group means an aromatic or non-aromatic heterocyclic group which contains at least one or more N atom(s) and optional O or S atom(s), such as azetidinyl, pyrrolidinyl, piperidinyl, imidazolydinyl, pyrazolidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, morpholinyl, thio morpholinyl, thiazolinyl, oxazolinyl, imidazolinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isooxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, imidazolyl, triazolyl, and tetrazolyl. Preferred is a non-aromatic group, esp., a 4- to 6-membered N-containing saturated heterocyclic group such as azetidinyl (e.g., 3-azetidinyl), pyrrolidinyl (e.g., 3-pyrrolidinyl), and piperidinyl (e.g., 4-piperidinyl).
When the heterocyclic group is substituted, examples of the substituent include one or more of the same or different group(s) selected from halogen (e.g., F and Cl), hydroxy, hydroxy(lower)alkyl (e.g., hydroxymethyl, 1-hydroxyethyl, and 2-hydroxyethyl), optionally substituted amino (wherein the substituent is lower alkyl (e.g., methyl, ethyl, and propyl) or the like), optionally substituted carbamoyl (wherein the substituent is e.g., methyl and ethyl), lower alkyl (e.g., methyl and ethyl), lower alkoxy (e.g., methoxy, ethoxy, and propoxy), imino(lower) alkyl (e.g., iminomethyl and 1-imonoethyl), halogenated(lower)alkyl (e.g., trifluoromethyl), optionally esterfied carboxy, cyano, nitro, lower alkylthio (e.g., methylthio), lower alkoxyalkoxy (e.g., methoxymethoxy and ethoxyethoxy), lower alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), acylamino (e.g., acetylamino) and the like. In addition to those, the possible substituents on the N atom of the heterocyclic group include the above-described amino-protecting group.
R4 is preferably one, two or more of the same or different group(s) selected from hydrogen, optionally substituted(lower)alkyl (wherein the substituent is preferably optionally substituted amino (wherein the substituent is lower alkyl (e.g., methyl), hydroxy(lower)alkyl (e.g., 2-hydroxyethyl), sulfonic acid-oxy(lower)alkyl (e.g., 2-sulfonic acid-oxyethyl) or the like), lower alkoxycarbonyl (e.g., t-butoxycarbonyl), carbamoyl, lower alkylcarbamoyl(e.g., methylcarbamoyl), hydroxy, halogen, lower alkoxy (e.g., methoxy), the above-described amino-protecting group (e.g., Boc, PMB) or the like), N-containing heterocyclic group and the like, more preferably hydrogen, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94(CH2)2CH3, xe2x80x94(CH2)3NH2, xe2x80x94(CH2)3NHCH3, xe2x80x94(CH2)3NH(CH2)2OH, azethidinyl, pyrrolidinyl or piperidinyl, and most preferably hydrogen, xe2x80x94(CH2)3NH2, xe2x80x94(CH2)3NHCH3 or xe2x80x94(CH2)3NH(CH2)2OH.
(Definition of R5)
The lower alkyl, by itself or as part of lower alkylthio, is the same as that defined for R2. The lower alkoxy is the same as that defined for R3.
Examples of the substituent on the lower alkyl, lower alkoxy or lower alkylthio include halogen (e.g., F, Cl, and Br), hydroxy, carboxy, cyano, amino, carbamoyloxy, sulfamoyl, lower alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), lower alkylthio(e.g., methylthio and ethylthio) and the like.
R5 is preferably hydrogen, methyl, methylthio or the like, and more preferably hydrogen.
R4 and R5 taken together may form lower alkylene in which an optional hetero atom(s) intervene. When the hetero atom is N, it may be substituted with lower alkyl or the like, resulting in that R4 and R5 taken together forms xe2x80x94(CH2)3xe2x80x94N(Me)xe2x80x94 for example.
The esters of compound (I) include an ester which is formed at the 4-carboxy part, e.g., an ester useful as an intermediate or a metabolic ester. Examples of the ester-residue include e.g., optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C3-C10 cycloalkyl, C3-C10 cycloalkyl(C1-C6)alkyl, optionally substituted C6-C10 aryl, optionally substituted C7-C12 aralkyl, di(C6-C10)arylmethyl, tri(C6-C10)arylmethyl, and substituted silyl.
Examples of the optionally substituted C1-6 alkyl include e.g., methyl, ethyl, n-propyl, n-butyl, t-butyl, n-pentyl, and n-hexyl, each may be substituted with benzyloxy, C1-4 alkylsulfonyl (e.g., methanesulfonyl), trimethylsilyl, halogen (e.g., F, Cl, and Br), acetyl, nitrobenzoyl, mesylbenzoyl, phthalimide, succinoylimide, benzenesulfonyl,phenylthio, di-C1-4alkylamino (e.g., dimethylamino), pyridyl, C1-4alkylsulfinyl (e.g., methanesulfinyl), cyano and the like. Such substituted C1-6 alkyl include e.g., benzyloxymethyl, 2-methanesulfonylethyl, 2-trimethylsilylethyl, 2,2,2-trichloroethyl, 2-iodoethyl, acetylmethyl, p-nitrobenzoylmethyl, p-mesylbenzoylmethyl, phthalimidemethyl, succinoylimidemethyl, benzenesulfonylmethyl, phenylthiomethyl, and 1-dimethylaminoethyl. The above C2-6 alkenyl includes e.g., vinyl, aryl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 1,1-dimethylaryl, 3-methyl and 3-butenyl. The above C3-10 cycloalkyl includes e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. The above C3-10 cycloalkyl(C1-6)alkyl includes e.g., cyclopropylmethyl, cyclopentylmethyl, and cyclohexylmethyl. The above C6-10 aryl includes e.g., phenyl, xcex1-naphthyl, 8-naphthyl, and biphenyl, each may be substituted with nitro, halogen (e.g., F, Cl, and Br) or the like, and such substituted aryl includes e.g., p-nitrophenyl and p-chlorophenyl. The above optionally substituted C7-12 aralkyl includes e.g., benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl and naphthylmethyl, each may be substituted with nitro, C1-4 alkoxy (e.g., methoxy), C1-4 alkyl (e.g., methyl, ethyl), hydroxy or the like. Such substituted group is exemplified by p-nitrobenzyl, p-methoxybenzyl (PMB), or 3,5-di-t-butyl-4-hydroxybenzyl. The above di(C6-10 aryl)methyl includes benzhydryl and the C6-10 arylmethyl includes trityl, and the substituted silyl includes trimethylsilyl and tert-butyldimethylsilyl, for example.
Examples of the pharmaceutically acceptable salt of compound (I) include salts formed with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions or the like, and inner salts. Examples of the inorganic base include alkali metal (e.g., Na and K) and alkaline earth metal (e.g., Mg). Examples of the organic base include procaine, 2-phenylethylbenzylamine, dibenzylethylenediamine, etanolamine, di etanolamine, tris(hydroxymethyl)aminomethane, polyhydroxyalkylamine, and N-methyl glucosamine. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of the organic acid include p-toluene sulfonic acid, methanesulfonic acid, formic acid, trifluoroacetc acid and maleic acid. Examples of the basic amino acid include lysine, arginine, ornithine and histidine. The quarternary ammonium cation on the 3-side chain of compound (I) may form an inner salt with the 4-COO group as a counter ion. When the group at the 4-position is COOH or COOR wherein R is a metal cation or ester-residue, the quarternary ammonium cation is combined with a counter ion. Compound (I) is preferably an inorganic salt, more preferably a salt of sulfuric acid, and most preferably mono sulfate in the light of the crystallinity, conservation stability, handling in pharmaceutical manufacturing or the like.
Prodrug means a derivative of compound(I), which has a chemically or metabolically decomposable group and is converted to a pharmaceutically active compound (I) by solvolysis or under physiological conditions in vivo. A method for selecting and preparing an appropriate prodrug-derivative is described in e.g., Design of Prodrugs, Elsevier, Amsterdam 1985.
When compound (I) has a carboxy group, examples of the prodrug include an ester derivative prepared by reacting an acidic original compound with a proper alcohol or an amide derivative prepared by reacting an acidic original compound with a proper amine. Preferred esters as the prodrug include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, tert-butyl ester, and morpholinoethylester. When compound (I) has a hydroxyl group, examples of the prodrug include an acyloxy derivative which is prepared by reacting a hydroxyl group-containing compound with a proper acyl halide or acid anhydride. Preferred acyloxy includes xe2x80x94OCOC2H5, xe2x80x94OCO(t-Bu), xe2x80x94OCOC15H31, xe2x80x94OCO(m-COONa-Ph), xe2x80x94OCOCH2CH2COONa, xe2x80x94OCOCH(NH2)CH3 and xe2x80x94OCOCH2N(CH3)2. When compound (I) has an amino group, examples of the prodrug include an amide derivative which is prepared by reacting an amino group-containing compound with a proper halogenated acid or mixed acid anhydride. Preferred amides include xe2x80x94NHCO(CH2)20CH3, xe2x80x94NHCOCH(NH2)CH3 and the like.
The solvate of compound (I) is preferably hydrate e.g., 0.5- to 10-hydrate, and more preferably 4-, 5-, 6-, 7-, or 8-hydrate. Particularly preferred is a crystalline monosufatexc2x74- to 8-hydrate. Compound (I) may be a solvate formed with i-propanol, ethanol, trifluoroacetic acid or the like.
Compound (I) is preferably a compound described in any of above (11) to (18), more preferably a compound (I) wherein X is N; R1 is amino; R2 is xe2x80x94CH2F; R3 is hydrogen; R4 is xe2x80x94(CH2)3NHCH3; R5 is hydrogen; and the wavy line means syn-isomerism or a salt thereof, esp. mono sulfate, for example. Among the sulfate, crystals are preferred to non-crystals in the light of their stability for pharmaceutical preparation or the like, and more preferred are crystalline hydrates such as 4- to 7- or 8-hydrate of monosulfate, esp. the 4- or 5-hydrate. These crystals are characterized by specific main peaks of the powder X-ray diffractometry.
Methods for preparing compound (I) are shown below.
(Method 1)
Compound (I) can be synthesized by reacting a 7-amino compound of the formula (II): 
wherein each symbol is the same as defined above, a ester or salt thereof (each hereinafter referred to as compound (II)) with a carboxylic acid of the formula(III): 
wherein each symbol is the same as defined above, or a reactive derivative thereof (each hereinafter referred to as compound (III)).
Examples of the ester or salt of compound (II) include the same as those mentioned for compound (I).
Examples of the reactive derivative of compound (III) include inorganic base salts, organic base salts, acid halides, acid azides, acid anhydrides, mixed acid anhydride, active amide, active ester, active thioester. The inorganic base includes alkaline metals (e.g., Na and K) and alkaline earth metals (e.g., Ca and Mg); The organic base includes trimethylamine, triethylamine, tert-butyldimethylamine, dibenzylmethylamine and benzyldimethylamine; the acid halide includes acid chloride and acid bromide; the mixed acid anhydride includes mixed monoalkylcarboxylic acid anhydride, mixed alphatic carboxylic acid anhydride, aromatic carboxylic acid anhydride, oraganic sulfonic acid anhydride, the active amide includes amide formed with heterocyclic compound containing N atom, for example. Examples of the active ester include organic phosphate esters (e.g., diethoxy phosphate ester and diphenoxy phosphate ester), p-nitrophenyl ester, 2,4-dinitrophenyl ester, cyanomethyl ester, and the active thioester includes esters formed with aromatic heterocyclicthio compound (e.g., 2-pyridilthio ester).
The above reaction may be carried out using an appropriate condensing agent, if necessary. Examples of the condensing agent include e.g., N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-thiocarbonyldiimidazole, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, 2-chloropyridiniummethyl iodine, and 2-fluoropyridiniummethyl iodine.
Examples of solvents used in the reaction include ethers (e.g., dioxane, THF, diethylether, tert-butylmethylether, and diisopropylether), esters (e.g., ethyl formate, ethyl acetate, and n-butyl acetate), halogenated hydrocarbons (e.g., dichloromethane, chloroform, and carbon tetrachloride), hydrocarbons (e.g., n-hexane, benzene, and toluene), amides (e.g., formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetoamide, and N-methylpyrrolidone), ketones (e.g., acetone and methylethylketone), nitryls (e.g., MeCN and propionitryl), dimethylsulfoxide, and water.
The amount of compound (III) is usually about 1-5 mol, preferably about 1-2 mol, per compound (II) 1 mol. The reaction may be carried out at about xe2x88x9280 to 80xc2x0 C., preferably about xe2x88x9240 to 50xc2x0 C.
Compound (II) is prepared, for example, by reacting a compound of the formula (Ixe2x80x2): 
wherein R6 is a leaving group (e.g., hydroxy, halogen (e.g., Cl, Br, I), carbamoyloxy, substituted carbamoyloxy, and acyloxy), an ester or salt thereof (hereinafter referred to as compound (IIxe2x80x2)) with an imidazo[4,5-b]pyridine compound of the formula (IV): 
wherein each symbol is the same as defined above, or a salt thereof (hereinafter referred to as compound(IV)).
Compound (IIxe2x80x2) may be prepared according to documents (e.g., JP(A) 60-231684 and JP(A) 62-149682). Examples of the acyloxy in R6 include acetoxy, chloroacetoxy, propionyloxy, butylyloxy, pivaloyloxy, and 3-oxobutylyloxy. Examples of above substituted carbamoyloxy include methylcarbamoyloxy and N,N-dimethylcarbamoyloxy. Examples of the salt of compound (IV) include inorganic acid addition salts (e.g., hydrochloride, hydrobromate, sulfate, nitrate, and phosphate) and organic acid addition salts (e.g., formate, acetate, trifluoroacetate, methanesulfonate, and p-toluenesulfonate).
(Method 2)
Compound (I) is prepared by reacting a compound of the formula (V): 
wherein each symbol is the same as defined above, an ester or salt thereof (hereinafter referred to as compound (V)) with the above-described compound (IV).
Examples of salts or esters of the compound (V) are the same as those of compound (I).
Examples of solvents used in the reaction are the same as those used in the above-described Method (1). In addition, compound (IV) may be used also as a solvent.
The amount of compound (IV) is usually about 1-5 eq. mol, preferably about 1-3 eq. mol, per compound (V). The reaction is usually conducted at about 0-100xc2x0 C., preferably about 10-80xc2x0 C., within several minutes to several hours.
In the process, a reaction mediator mat be added, such as iodides (e.g., NaI and KI) and thiocyanate (e.g., sodium thiocyanate and potassium thiocyanate). When R6 is hydroxy, the reaction may be conducted in the presence of various phosphorus compounds according to JP(A) Kokai S58-43979.
(Method 3)
Compound (I), provided R2 is not hydrogen, can be obtained by reacting a compound of the formula(VI): 
wherein each symbol is the same as above, an ester or, a salt thereof (hereinafter referred to as compound(VI)) with a compound of the formula: R2OH wherein R2 is the same as above, or a reactive derivative thereof. The reactive derivative of R2OH includes a compound of the formula: R2Z wherein Z is a leaving group such as halogen, methanesulfonyloxy, and benzenesulfonyloxy.
(3-1) Reaction Using R2OH
Compound (VI) and R2OH are reacted in the presence of an appropriate dehydrating agent. Examples of the dehydrating agent include phosphorus oxychloride, thionyl chloride, dialkyl azodicarboxylate/phosphine, and N,Nxe2x80x2-dicyclohexylcarbodiimide. The reaction solvate includes e.g., the above-described ethers and hydrocarbons. The amount of compound R2OH is usually about 1 to 1.5 mol per compound (VI) 1 mol. The reaction temperature is usually about 0 to 50xc2x0 C.
(3-2) Reaction Using R2Z
R2Z and compound (VI) are reacted, if necessary, in the presence of a base. The reaction solvates include e.g., the above-described ethers, esters, halogenated hydrocarbons, hydrocarbons, amides, ketones, nitryls, alcohols, and water. The base includes for example, alkali metal salt (e.g., Na2CO3, NaHCO3, K2CO3), alkali metal hydroxide (e.g., NaOH, KOH). The amount of R2Z is usually about 1 to 5 mol per compound(VI) 1 mol. The reaction temperature is about xe2x88x9230 to 100xc2x0 C., preferably about 0 to 80xc2x0 C. The above-described compound (IV) is known or new. Even when the compound (IV) is new, it can readily be synthesized through reactions well known to a person skilled in the art. A representative method is shown below. 
Compound (IV) can be prepared by reacting compound (VII) with R4Xxe2x80x2 (R4 is the same as defined above, provided R4 is not H. Xxe2x80x2 is a leaving group (e.g., Iodine and methanesulfonyloxy)) in the presence of a base (e.g., NaH and CsCO3). The reaction can also be conducted under Mitsunobu""s reaction condition: R4OH/dialkyl axodicarboxylate/phosine. The reaction solvates include e.g., the above-described ethers and amides. The reaction temperature is about xe2x88x9220 to 150xc2x0 C., preferably about 0 to 50xc2x0 C.
The obtained compound (IV) may further be chemically modified to other compounds. Other methods B to F are shown below. 
(Wherein Each Symbol is the Same as Defined Above)
Compound (V) and pridine derivative (VIII) are reacted to give compound (IX) (Step 1), then which is cyclized at the 3-side chain portion (Step 2), to give compound (I) (see, Reference Examples 31 to 33 and Examples 29 to 32.)
Step 1 reaction may be carried out according to the above Method 2. The 4-carboxy group of compound (IX) may be protected when N+ of the 3-side chain is combined with a counter ion. The cyclization of Step 2 is preferably conducted in the presence of an acid. Examples of the acid include inorganic acids (e.g., HCl, H2SO4, H2PO3, HNO3, toluene sulfonate, and methane sulfonate) and organic acids (e.g., HCO2H and CH3CO2H). Preferred is H2SO4 for the yield, handling or the like. The temperature of the acid-treating reaction is about xe2x88x9220 to about 100xc2x0 C., preferably about 0 to about 30xc2x0 C., and the reaction time is several minutes to several hours. The reaction solvates include acetic acid, ethyl acetate, acetonitrile, acetone, dimethylformamide (DMF), and tetrahydrofuran (THF). In a preferred embodiment of the Step 2 cyclization, the amino-protecting group (e.g., PMB and Boc) or 4-carboxy-protecting group (e.g., PMB) of compound (IX) can be deprotected.
Prior to the above each reaction, a functional group such as amino, imino, hydroxy, and carboxy may be protected by a method well known to skilled persons and if necessary deprotected after the reaction.
Compound (I) shows a broad antibacterial spectrum and so it can be used for preventing or treating mammals (e.g., humans) for various diseases caused by pathogenic microorganisms, such as respiratory tract infection and genito-urinary tract infection. The characters of compound (I) include the following points:
(1) excellent activity against Gram-negative bacteriums
(2) excellent activity against Gram-positive bacteriums
(3) excellent activity against methicillin-resistant S. aureus (MRSA)
(4) excellent activity against Pseudomonas
(5) excellent in vivo dynamics: high blood drug concentration, long time action, and good tissue transplantatio; compound (I) is not liable to be metabolized, thus the urinary recovery of the non-metabolite is high.
(6) excellent in water-solubility and safety.
Compound (I) can be orally or parenterally administered in a form of injection, capsule, granule, or the like, and a preferred form is injection. The daily dosage can usually be varied in the range of about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg, which is administered in two to four divisions if necessary. The pharmaceutically acceptable carriers used to injections include e.g., distilled water, physiologic saline, and pH adjusting agents such as bases. For preparing capsules, granules, and tables, other pharmaceutically acceptable carriers can be used, such as excipients (e.g., starch, lactose, sucrose, calcium carbonate, calcium phosphate), binders (e.g., starch, Arabian gum, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose), and lubricants (e.g., magnesium stearate, talc).